The cutaneous T-cell lymphomas (Mycosis Fungoides and the Sezary Syndrome) comprise a group of indolent neoplasms of mature helper T-cells, the etiology of which is poorly understood. The clinical spectrum of these neoplasms varies from one of chronic skin involvement to one of aggressive disease with organ infiltration and circulating malignant T-cells. Since it has been suggested that early stage skin lesions comprise a polyclonal rather than a monoclonal population, it is unclear whether the disease arises from an event in a T-cell precursor, or whether it arises out of a T-cell response to an event, or possibly a viral infection, in an accessory cell. We are attempting to address this question by determining the clonal nature of early stage skin infiltration using PCR amplification and sequencing of T-cell receptor rearrangements in the skin. In addition, we are exploring the hypothesis that a retrovirus may be implicated in the pathogenesis of this disease by studying patient materials for retroviral- like sequences and by culturing cells from patients and attempting to isolate retroviral activity. Thus far, we have identified reverse transcriptase-like activity in cultured cells and in cocultivations of MF cells and permissive cell lines, and further characterization of this activity is underway. In addition, we have studied response to growth factors and cytotoxic activities of a number of pharmacologic agents in MF cells and in Hut 78, an MF cell line, in an attempt to derive new therapies for patients. We are currently exploring the therapeutic role of DDI in this disease.